27-Hydroxycholesterol Is an Estrogen Receptor β–Selective Negative Allosteric Modifier of 17β-Estradiol Binding

Starkey, Nicholas J.E.; Li, Yufei; Drenkhahn-Weinaug, Sara K; Liu, Jinghua; Lubahn, Dennis B.

doi:10.1210/en.2018-00081

Cited by 20 publications

(25 citation statements)

References 63 publications

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“…The effect of 27HC was observed not only in H1395 cells, but also in LLC cells that are transfected with ERβ (Supplemental Figure 1 ), indicating the effect of 27HC is not H1395 cell-specific. Recently, a report indicated that 27HC acts as a negative modulator of ERβ ( 40 ). In our study, both 27HC and E 2 promoted H1395 cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol

et al. 2018

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27-hydroxycholesterol (27HC) is an abundant cholesterol metabolite in human circulation and promotes breast cancer cell proliferation. Although lung is one of the organs that contain high levels of 27HC, the role of 27HC in lung is unknown. In this study, we found that 27HC promotes lung cancer cell proliferation in an estrogen receptor β (ERβ)-dependent manner. The expression of 27HC-generating enzyme CYP27A1 is higher in lung cancer cells than in normal lung cells. Treatment with 27HC increased cell proliferation in ERβ-positive lung cancer cells, but not in ERα-positive or ER-negative cells. The effect on cell proliferation is specific to 27HC and another oxysterol, 25-hydroxycholesterol that has a similar oxysterol structure with 27HC. Moreover, among ligands for nuclear receptors tested, only estrogen had the proliferative effect, and the effect by 27HC and estrogen was inhibited by ERβ-specific, but not ERα-specific, inhibitors. In addition, the effect by 27HC was not affected by membrane-bound estrogen receptor GPR30. Interestingly, despite the high expression of CYP27A1, endogenously produced 27HC was not the major contributor of the 27HC-induced cell proliferation. Using kinase inhibitors, we found that the effect by 27HC was mediated by the PI3K-Akt signaling pathway. These results suggest that 27HC promotes lung cancer cell proliferation via ERβ and PI3K-Akt signaling. Thus, lowering 27HC levels may lead to a novel approach for the treatment of lung cancer.

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol

et al. 2018

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“…Experimental studies identified 27HC as an endogenous selective estrogen receptor modulator (SERM) [2]. 27HC binds to both the estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) [2,3], though with greater affinity for ERβ [3]. Although the precise roles of ERβ in breast cancer remain to be delineated [4], ERβ was demonstrated to be expressed in a majority of breast cancers, including those lacking ERα expression.…”

Section: Introductionmentioning

confidence: 99%

Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort

et al. 2020

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Background: Experimental and epidemiological studies demonstrate a role for 27-hydroxycholesterol (27HC) in breast cancer development, though results are conflicting. Cholesterol 27-hydroxylase (CYP27A1) and oxysterol 7alpha-hydroxylase (CYP7B1) regulate 27HC concentrations, while differential expression of the liver X receptor (LXR) and estrogen receptor beta (ERβ) may impact the association between 27HC and breast cancer risk. Methods: We evaluated correlates of tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ and the association between circulating prediagnostic 27HC concentrations and breast cancer risk by marker expression in a nested casecontrol study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort including 287 breast cancer cases with tumor tissue available. Tumor protein expression was evaluated using immunohistochemistry, and serum 27HC concentrations quantified using liquid chromatography-mass spectrometry. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Results: A higher proportion of CYP7B1-positive cases were progesterone receptor (PR)-positive, relative to CYP7B1negative cases, whereas a higher proportion of ERβ-positive cases were Bcl-2 low, relative to ERβ-negative cases. No differences in tumor tissue marker positivity were observed by reproductive and lifestyle factors. We observed limited evidence of heterogeneity in associations between circulating 27HC and breast cancer risk by tumor tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ, with the exception of statistically significant heterogeneity by LXR-β status in the subgroup of women perimenopausal at blood collection (p = 0.02). Conclusion: This exploratory study suggests limited associations between tumor marker status and epidemiologic or breast cancer characteristics. Furthermore, the association between circulating 27HC and breast cancer risk may not vary by tumor expression of CYP27A1, CYP7B1, LXR-β, or ERβ.

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“…This heterodimer complex can directly associate with ERα and ERβ, recruiting the co-activator p300, which then results in ligand independent activation of estrogen receptors [48]. Recently, our lab reported an alternate binding site present in ERβ, which can allosterically regulate ERβ’s activity [49]. It is possible that DIM binds and activates ER from an alternate binding site but does not allosterically influence the binding affinity of E2 in the orthosteric site in an appreciable way.…”

Section: Discussionmentioning

confidence: 99%

3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer

Mahloch

Starkey

et al. 2019

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3,3'-Diindolylmethane (DIM) is an acid-derived dimer of indole-3-carbinol, found in many cruciferous vegetables, such as broccoli, and has been shown to inhibit prostate cancer (PCa) in several in vitro and in vivo models. We demonstrated that DIM stimulated both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) transcriptional activities and propose that ERβ plays a role in mediating DIM's inhibition on cancer cell growth. To further study the effects of DIM on inhibiting advanced PCa development, we tested DIM in TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. The control group of mice were fed a high fat diet. Three additional groups of mice were fed the same high fat diet supplemented with 0.04%, 0.2% and 1% DIM. Incidence of advanced PCa, poorly differentiated carcinoma (PDC), in the control group was 60%. 1% DIM dramatically reduced PDC incidence to 24% (p=0.0012), while 0.2% and 0.04% DIM reduced PDC incidence to 38% (p=0.047) and 45% (p=0.14) respectively. Though DIM did affect mice weights, statistical analysis showed a clear negative association between DIM concentration and PDC incidence with p=0.004, while the association between body weight and PDC incidence was not significant (p=0.953). In conclusion, our results show that dietary DIM can inhibit the most aggressive stage of prostate cancer at concentration lower than previously demonstrated, possibly working through an estrogen receptor mediated mechanism.(PDC) prevention. Previously our lab demonstrated that in TRAMP mice, ERα stimulated advanced prostate cancer while ERβ inhibited it [34]. In this case, we examined DIM's effect on estrogen receptor which suggested a role for ER in DIM's prevention of advanced prostate cancer. Materials and MethodsReagents 17β-estradiol (E2) was purchased from Sigma Aldrich (St. Louis, MO). DIM used in cell culture was purchased from Sigma Aldrich (St. Louis, MO); DIM used in animal studies was purchased from BulkSupplements.com (Henderson, NV) and its purity was verified by HPLC as >98%. ICI 182,780 was a gift from Dr. Rex Hess (UI-UC). AnimalsAnimal study protocols were approved by the Animal Care and Use Committee of the University of Missouri and all institutional guidelines for animal welfare and use were followed. Study mice were bred by crossing male FVB TRAMP mice with C57BL/6 female mice to generate F1 C57/FVB hybrid male TRAMP mice as described previously [35]. TRAMP positive F1 males received study diets starting from 6 weeks of age, as TRAMP mice begin forming tumors after the onset of puberty (usually around 8 weeks of age) and continued until study termination. Study mice were housed 2-3 per micro-isolator cages and given free access to food and water, under the condition of a daily light: dark cycle of 12:12h, ambient temperature at 21℃, and humidity at 50% throughout the study. Mice were weighed every week to monitor body weight and tumor

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27-Hydroxycholesterol Is an Estrogen Receptor β–Selective Negative Allosteric Modifier of 17β-Estradiol Binding

Cited by 20 publications

References 63 publications

Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol

Estrogen Receptor Beta-Mediated Modulation of Lung Cancer Cell Proliferation by 27-Hydroxycholesterol

Circulating 27-hydroxycholesterol and breast cancer tissue expression of CYP27A1, CYP7B1, LXR-β, and ERβ: results from the EPIC-Heidelberg cohort

3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer

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